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Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease with multifactorial etiology, unsatisfactory treatment, and a necessity for broad-spectrum active substances for cure. The mucus from Helix aspersa snail is a mixture of bioactive molecules with antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects. So far there are no data concerning the capacity of snail extract (SE) to affect neurodegenerative disorders. Objective: The effects of SE from Helix aspersa on learning and memory deficits in Alzheimer’s type dementia (ATD) induced by scopolamine (Sco) in male Wistar rats were examined and some mechanisms of action underlying these effects were evaluated. Methods: SE (0.5 mL/100 g) was applied orally through a food tube for 16 consecutive days: 5 days before and 11 days simultaneously with Sco (2 mg/kg, intraperitoneally). At the end of Sco treatment, using behavioral methods, we evaluated memory performance. Additionally, in cortex and hippocampus the acetylcholinesterase (AChE) activity, acetylcholine and monoamines (dopamine, noradrenaline, and serotonin) content, levels of main oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) were determined. Results: We demonstrated that, according to all behavioral tests used, SE significantly improved the cognitive deficits induced by Sco. Furthermore, SE possessed AChE inhibitory activity, moderate antioxidant properties and the ability to modulate monoamines content in two brain structures. Moreover, multiple SE applications not only restored the depressed by Sco expression of CREB and BDNF, but significantly upregulated it. Conclusion: Summarizing results, we conclude that complex mechanisms underlie the beneficial effects of SE on impaired memory in Alzheimer’s type dementia.

This study evaluates some of the neuromodulatory mechanisms of the memory loss preventive effect of alpha-lipoic acid (ALA) in a scopolamine (Sco)-induced rat model of Alzheimer's disease (AD) type dementia. Our results confirmed that Sco administration induces significant memory impairment, worsens exploratory behaviour and habituation, increases acetylcholinesterase (AChE) activity, and induces pathological monoamine content changes in the prefrontal cortex and hippocampus. ALA administration largely prevented Sco-induced memory impairment. It also improved exploratory behaviour and preserved habituation, and it decreased AChE activity, reversing it to control group levels, and corrected aberrant monoamine levels in the prefrontal cortex and hippocampus. According to the data available, this is the first time that ALA-induced changes in AChE and monoamine levels in the prefrontal cortex and hippocampus (brain structures related to learning and memory) have been demonstrated in a Sco-induced rat model of AD type dementia.

Background: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer’s disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). Objective: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. Methods: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. Results: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. Conclusion: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal–adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer’s models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs’ neuroprotective properties in dementia. Methods: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. Results: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. Conclusion: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.

The neuroprotective capacity of newly synthesized amantadine derivative tyrosinyl-amantadine (Tyr-Am) with expected antiparkinsonian properties was evaluated in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Male Wistar rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned control group, 6-OHDA-lesioned rats pretreated for 6 days with Tyr-Am (16 mg/kg administered intraperitoneally, i.p.), and 6-OHDA-lesioned rats pretreated for 6 days with amantadine (40 mg/kg i.p.), used as a referent. On the first, second and third week post-lesion, the animals were subjected to some behavioral tests (apomorphine-induced rotation, rotarod, and passive avoidance test). The acetylcholinesterase (AChE) activity and key oxidative stress parameters including lipid peroxidation levels (LPO) and superoxide dismutase (SOD) were measured in brain homogenates. The results showed that the neuroprotective effect of Tyr-Am was comparable to that of amantadine, improving neuromuscular coordination and learning and memory performance even at a 2.5-fold lower dose. Tyr-Am demonstrated significant antioxidant properties via decreased LPO levels but had no effect on AChE activity. We can conclude that the newly synthesized amantadine derivative Tyr-Am demonstrated significant antiparkinsonian activity in a 6-OHDA experimental model.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit β-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine.

Previous evidence has shown a link between neurodegenerative diseases, including Parkinson's disease (PD), and melatonin. The data in the literature about the impact of the hormone under different experimental PD conditions are quite controversial, and its effect on memory impairment in the disease is very poorly explored. The current research was aimed at investigating the role of melatonin pretreatment on memory and motor behavior in healthy rats and those with the partial 6-hydroxydopamine (6-OHDA) model of PD. All rodents were pretreated with melatonin (20 mg/kg, intraperitoneally) for 5 days. At 24 h and 7 days after the first treatment for healthy rats, and at the second and third week post-lesion for those with PD, the animals were tested behaviorally (apomorphine-induced rotations, rotarod, and passive avoidance tests). The neurochemical levels of dopamine (DA), acetylcholine (ACh), noradrenaline (NA), and serotonin (Sero) in the brain were also determined. The results showed that in healthy animals, melatonin pretreatment had amnestic and motor-suppressive effects and did not change the levels of measured brain neurotransmitters. In animals with PD, melatonin pretreatment exerted a neuroprotective effect, manifested as a significantly decreased number of apomorphine-induced rotations, reduced number of falls in the rotarod test, and improved memory performance. The brain DA and ACh concentrations in the same animals were restored to the control levels, and those of NA and Sero did not change. Our results demonstrate a beneficial effect of melatonin on memory and motor disturbance in 6-OHDA-lesioned rats.

Close functional and anatomical interactions between the neurotensin (NT) and dopamine (DA) systems suggest that NT could be associated with Parkinson’s Disease (PD). However, clinical use of NT is limited due to its rapid degradation. This has led to the synthesis of a number of new NT fragment 8-13 [NT(8-13)] analogues, such as NT2 and NT4, to avoid the fast biodegradation of NT. The aim of this study was to investigate the neuroprotective effects of NT2 and NT4 on an experimental model of Parkinson’s disease in rats induced with 6-hydroxydopamine (6-OHDA) treatment, producing striatal lesions. Wistar male rats were divided into different groups: a sham-operated (SO) group, a striatal 6-OHDA-lesioned control group, two groups of 6-OHDA-lesioned rats treated for 5 days with NT2 or NT4 (10 mg/kg, intraperitoneally) and a NT-treated group as reference. During the first and second week post lesion the animals were subjected to a number of behavioral tests (apomorphine-induced rotations, rotarod, passive avoidance test), and brain tissue was evaluated histologically and also assessed for DA levels. The results showed that both the number of apomorphine-induced rotations and falls (rotarod test) increased in the 6-OHDA group relative to the SO group. At the same time, the 6-OHDA-treated group showed significant memory impairment, based on the to step-through test, compared to the SO group. Treatment with NT2 and NT4 significantly decreased the number of apomorphine-induced rotations and improved the memory of lesioned animals, with these NT analogues demonstrating better neuroprotective and neuromodulatory effects than NT. DA content in the brain of the PD rats treated with NT2 and NT4 increased, possibly due to attenuation of the loss of DA-ergic neurons. NT2 and NT4 were found to easily penetrate the blood–brain barrier and they showed a better stability than the reference NT neuropeptide. In conclusion, the NT approach represents an attractive strategy for the treatment of neurodegenerative disease.

Vasoactive intestinal peptide (VIP) was administered in a model of zymosan-induced generalized inflammation (ZIGI). Its beneficial action was associated with reduced TNF-α and increased IL-10 production, lowered levels of creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin in circulation. VIP diminished the level of RANTES and MIP-1α in peritoneal exudate and circulation. The neuropeptide inhibited NO release from stimulated peritoneal macrophages. Decreased spleen, liver and kidney enlargement and less pathological changes in liver were observed. The effect of VIP was attenuated by pretreatment with VIP antagonist (anti-VIP) before the induction of shock.

The modulation of striatal cholinergic neurons by somatostatin (SOM) was studied by measuring the release of acetylcholine (ACh) in the striatum of freely moving rats. The samples were collected via a transversal microdialysis probe. ACh level in the dialysate was measured by the high performance liquid chromatography method with an electrochemical detector. Local administration of SOM (0.1, 0.5 and 1 microM) produced a long-lasting and concentration-dependent increase in the basal striatal ACh output. The stimulant effect of SOM was antagonized by the SOM receptor antagonist cyclo(7-aminopentanoyl-Phe-D-Trp-Lys-Thr[BZL]) (1 microM). In a series of experiments, we studied the effect of 6,7-dinitroquinoxaline-2, 3-dione (DNQX), a selective non-NMDA (N-methyl-D-aspartate) glutamatergic antagonist, on the basal and SOM-induced ACh release from the striatum. DNQX, 2 microM, perfused through the striatum had no effect on the basal ACh output but inhibited the SOM (1 microM)-induced ACh release. The non-NMDA glutamatergic receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3- benzodiazepine (GYKI-52466), 10 microM, antagonized the SOM (1 microM)-induced release of ACh in the striatum. Local administration of the NMDA glutamatergic receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), 100 microM, blocked SOM (1 microM)-evoked ACh release. Local infusion of tetrodotoxin (1 microM) decreased the basal release of ACh and abolished the 1 microM SOM-induced increase in ACh output suggesting that the stimulated release of ACh depends on neuronal firing. The present results are the first to demonstrate a neuromodulatory role of SOM in the regulation of cholinergic neuronal activity of the striatum of freely moving rats. The potentiating effect of SOM on ACh release in the striatum is mediated (i) by SOM receptor located on glutamatergic nerve terminals, and (ii) by NMDA and non-NMDA glutamatergic receptors located on dendrites of cholinergic interneurones of the striatum.

3-Aminocycloalkanespiro-5-hydantoins were synthesized and their biological activity was studied. In contrast to hydantoins, these compounds failed to induce either anticonvulsive effects in the central nervous system or inhibitory effects on cholinergic contractions in the enteric nervous system. However, they exerted well pronounced, atropinsensitive, contractile effects on the guinea-pig ileum longitudinal muscle preparations. Structure–activity relationships established allow the assumption that: (i) the reduction of the ring size in the molecule of the spirohydantoins leads to an increase in the potency of the respective analogue to induce contractile effect; (ii) the introduction of NH 2 in position 3 increases the ability of all the compounds studied to exert contractions; (iii) the enlargement of the ring leads to: (1) an increase of the degree of desensitization of the preparations; and (2) a decrease (except 1a ) of the potency of the analogues to exert contractile effects.

The effects of the non-N-methyl-D-aspartate (NMDA) agonist quisqualate (QUIS) and selective AMPA/kainate receptor antagonist 1-(aminophenyl)-methyl-7, 8-methyilendioxy-5H-2,3-benzodiazepine (GYKI 52466) on the release of acetylcholine (ACh) from the hippocampus and striatum of freely moving rats were studied by transversal microdialysis. Acetylcholine level in the dialisate was measured by the high performance liquid chromatography (HPLC) method with an electrochemical detector. The QUIS (100 microM) perfused through the striatum induced an increase of extracellular ACh level (250%) which lasted for over 1h and gradually returned to basal values. Local perfusion of GYKI 52466 (10-100 microM) to the striatum did not change the basal release of ACh. GYKI 52466 (10 microM) administered together with QUIS (100 microM) in he striatum antagonized the stimulant effect of QUIS on the ACh release. Local administration of the QUIS (100 microM) through the microdialysis fiber implanted in the hippocampus, caused a long lasting increase of extracellular hippocampal ACh level (360%) which was reversed when the drug was withdrawn from the perfusion solution. The stimulant effect of QUIS was antagonized by concomitant perfusion of GYKI (10 microM). No effect was seen on the basal ACh release when GYKI (10-100 microM) was perfused through the hippocampus. Local perfusion with tetrodotoxin (1 microM) decrease the basal release of ACh and prevented the QUIS-induced increase of ACh both in the hippocampus and striatum. Our in vivo neurochemical results indicate that hippocampal and striatal cholinergic systems are regulated by non-NMDA (probably AMPA) glutamatergic receptors located in the hippocampus and striatum.